Obesity and non-insulin dependent diabetes mellitus (NIDDM) are both characterized by increased gluconeogenesis, which correlates well with increased levels of free fatty acids (FFA) in the two states. However, net hepatic glucose output (HGO) is increased only in patients with NIDDM and not in obese, non-diabetic patients. Since HGO is the sum of gluconeogenesis and glycogenolysis, one must conclude that a compensatory fall in glycogenolysis is responsible for the normal HGO of obesity. Moreover, the increased synthesis of glucose-6-phosphate (G-6-P) derived from gluconeogenesis is a likely signal restraining glycogenolysis so that HGO is not increased in the obese non-diabetic subject. This compensatory mechanism may be lost in the diabetic patient. The studies outlined in this proposal have been designed to examine this hypothesis. Changes in HGO and gluconeogenesis will be assessed by infusion of [3-3H]-glucose and [U-14C]-alanine. The putative fall in glycogenolysis under conditions of increased gluconeogenesis will be examined by increasing the availability of FFA (a known gluconeogenic promoter) by infusion of Intralipid and heparin in normal volunteers. Impaired suppression of glycogenolysis in patients with NIDDM will be unmasked by: 1) comparing the dose-response relationship of increasing FFA to change in gluconeogenesis and HGO in normal, obese non-diabetic and obese diabetic subject and 2) examining the acute effect of decreased FFA stimulated gluconeogenesis on HGO (and glycogenolysis) in obese diabetic and non-diabetic subjects using a carnitine palmitoyl transferase-I inhibitor. The paradoxical effects of obesity and NIDDM on liver glycogen content during a 3-day fast will be compared, and the use of glucagon administration to semiquantitatively assess glycogenolysis after a 3-day fast will be ethanol infusion in tracer methodology and by suppression of gluconeogenesis with ethanol infusion in obese, non-diabetic subjects. Studies are also planned to examine in detail the potential sites of FFA- mediated regulation of gluconeogenesis and the effect of increased levels of FFA on the direction of isotopic dilution in the TCA cycle.